The indication of growth hormone (GH) replacement has gradually been expanding beyond the original indication for the growth hormone deficiency. The current list of GH replacement includes several genetic disorders characterized by the short stature such as Turner syndrome, Prader-Willi syndrome, and Noonan syndrome. In the Prader-Willi syndrome, GH is expected to be effective in the improvement of the body composition as well as the linear body growth (see, Mogul, H. R. et al., J Clin Endocrinol Metab 93 (4), 1238-1245 (2008)). Based on the efficacy results from the randomized studies, GH was approved by the U.S. Food and Drug Administration for treatment of the idiopathic short stature in children, whose predicted adult height is less than 2.25 SDS (see, Leschek, E. W. et al., J Clin Endocrinol Metab 89 (7), 3140-3148 (2004); and Wit, J. M. et al., J Pediatr 146 (1), 45-53 (2005)). The other indication of GH includes wasting from AIDS (Storer T W, W. L., et al., J Clin Endocrinol Metab. 90 (8), 4474-4482. (2005)). Given the broad range of biological benefits of GH, the expansion of GH indications is expected to continue.
On the other hand, one of the challenges in GH application is the compliance issue. While daily subcutaneous injections are needed for maintaining the clinical efficacy of GH, this has not been favored by the patients, especially the pediatric patients, leading to early termination of the therapy (Coste, J. et al., BMJ 315 (7110), 708-713 (1997)). In this respect, an inhalable formulation of GH can be considered as a potential alternative. The lung is an unique portal for systemic drug delivery because of the large surface area for drug absorption (˜100 m2 in adults) (Patton, J. S., Advanced Drug Delivery Reviews 19 (1), 3 (1996)), good epithelial permeability, and a rich blood supply (Schanker, L. L. S., Biochemical pharmacology 27 (4), 381-385 (1978); and Patton, J. S., Proc Am Thorac Soc 1 (4), 338-344 (2004)).
Furthermore, drugs deposited in the lungs face relatively lower concentrations of drug-metabolizing enzymes than those delivered orally (Patton, J. S., Advanced Drug Delivery Reviews 19 (1), 3 (1996); and Ann, T. et al., Journal of pharmaceutical sciences, 92 (6), 1216-1233 (2003)). This property is particularly beneficial for delivery of protein drugs like GH, whose administration is currently limited to parenteral routes. Accordingly, the lung has gained increasing attention as a potential site for systemic delivery of drugs with poor oral bioavailability, as evident from recent advancement of inhalable insulin (See, Patton, J. S. & Byron, Nature Reviews Drug Discovery 6, 67-74 (2007); White, S. S. et al., Diabetes technology & therapeutics 7 (6), 896-906 (2005); and Pearson, J., Drug Delivery Report Spring/Summer, 19-21 (2006)). Although it was withdrawn from the market by the manufacturer a year after launch, patient satisfaction with inhaled insulin was quite high compared with injections, particularly among patients with needle anxiety (Brunton, S., Am J Med, 121 (6 Suppl), S35-41 (2008)).
A recent study comparing the effects of the inhaled GH and the subcutaneous GH in children with the GH deficiency was encouraging and promising. They reported that the inhaled GH was well tolerated and resulted in dose-dependent increases in serum GH and IGF-I levels. No significant changes in pulmonary functions were observed. However, the mean relative bioavailability for the inhaled GH was only 3.5% and the mean relative biopotency, based on IGF-I response, was 5.5% (Walvoord, E. C. et al., J Clin Endocrinol Metab 94 (6), 2052-2059 (2009)). These results suggest that a larger amount of GH will be needed in order to achieve the same clinical effects as subcutaneously injected GH.
Meanwhile, the N-methyl-D-aspartate class of glutamate (NMDA) receptors is involved in several physiological and pathophysiological processes, including synaptic plasticity, ischemia, neurodegeneration, and convulsions (Furukawa, H. et al. 2005, Nature 438: 185-192). And the NMDA receptor, are thought to have an important role in the induction of long-term potentiation (LTP), which is believed to be one of the required mechanisms for the development of memory at a synaptic level. The NMDA receptor subunits NR1 and NR2A-D have important roles in brain plasticity and behavior. NR1, NR2A and NR2B have been specially linked with hippocampal synaptic plasticity and learning parameters. This NMDA receptor-PSD-95 complex is associated with the induction of LTP and synaptic plasticity in the dentate gyrus area of the hippocampus.
Further, NMDA receptor hypofunction is implicated in a range of cognitive and behavioral functions of animals and humans (see, Cao, X. et al., Eur J Neurosci 25 (6), 1815-1822 (2007); and Ng D, P. G., PLoS Biol 7 (2), 41 (2009)). There is strong evidence that the NMDA receptors preferentially affect the neural mechanisms regulating the efficiency of encoding and consolidation into longer-term memorystorage (Clark, R. E., Hippocampus 15 (2), 260-272 (2005)). Severe NMDA receptor hypofunction can produce clinical syndromes including core features of psychosis, schizophrenia as well as dissociation (Li F, T. J., N Engl J Med. 361 (3), 302-303 (2009)).
The present inventors have endeavored to develop a safe and effective inhalable formulation comprising growth hormone (GH) and have found that said formulation can be effectively used in the treatment of an NMDA receptor hypofunction-related disease.